1. Field of the Invention
The invention relates to new annelated dihydropyridinoacetic acid derivatives, processes for preparing them and pharmaceutical compositions containing these compounds.
2. Description of the Related Art including information disclosed under 37 CFR 1.97 and 1.98.
Dihydroisoquinolines are known from EP-A 37 934. The compounds specified therein are cardiotonically active and have the effects of increasing contractility and influencing blood pressure. They have been proposed for improving blood circulation through the tissues.and for improving the oxygen supply to the tissues. These possible uses are based on the vascular activity of the compounds. EP-A 251 194 and EP-A 288 048 describe how carbocyclically and heterocyclically annelated dihydropyridines have a cardioprotective or cerebroprotective activity and constitute an entirely new type of Ca-antagonistic compounds. WO 92/11010 describes the use of such compounds for cerebroprotective agents, for treating chronic inflammatory processes and for inhibiting blood clotting and blood platelet aggregation.
The present invention relates to new carbocyclically and heterocyclically annelated dihydropyridines and the pharmaceutical use of these compounds. The new compounds have valuable therapeutically useful properties. They may be used as cardioprotective agents, as cerebroprotective agents (particularly for treating patients who have suffered a stroke or are in danger of suffering a stroke) and as agents for treating chronically inflammatory processes (e.g. bronchial asthma and arthritis). These compounds may also be used as agents with an antiproliferative effect and as agents for treating ulcerative colitis and Crohn""s disease.
The invention.relates to compounds of general formula I 
wherein
A denotes a benzo, indolo or thieno group;
wherein, if A is benzo, m is 2 or 3 (preferably 2, whilst the two R2s are in positions 6 and 7) and the substituents R2 independently of each other denote hydroxy, (C1-4)alkoxy, benzyloxy, halogen (F, Cl, Br, I), (C1-4)alkyl, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R2 may together represent xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94; and if A is indolo or thieno,
m is zero;
R1 denotes thienyl or the group 
xe2x80x83wherein
R7, R8 and R9 independently of one another may represent methyl, ethyl, propyl, phenyl or benzyl, whilst not more than 2 of the substituents can simultaneously represent phenyl or benzyl;
R3 and R4 independently of each other have one of the following meanings:
(a) hydrogen,
(b) branched or unbranched C3-6-alkenyl,
(c) branched or unbranched C3-6-alkynyl, or
(d) branched or unbranched C1-12-alkyl, wherein the alkyl may be substituted by
hydroxy,
(C1-4)alkoxy,
di(C1-4)alkylamino,
furyl,
pyridyl,
pyrrolidinyl, N-methylpyrrolidinyl,
morpholino,
indolyl,
nitrilo,
thienyl,
adamantyl,
cyclohexyl,
phenoxy,
naphthyloxy or phenyl, [whilst this phenyl or the phenyl contained in the phenoxy group may be mono-, di- or trisubstituted by hydroxy, (C1-4)alkoxy, benzyloxy, halogen (F, Cl, Br, I), CF3, N3, CN, (C1-4)alkyl, adamantyl, xe2x80x94SO2NH2, xe2x80x94NHCOCH3, xe2x80x94NHSO2CH3 or CH3SO2Oxe2x80x94 or by the bridge xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94;] or by two unsubstituted phenyl groups;
or R3 represents hydrogen and R4 represents cyclohexyl, phenyl (whilst this phenyl may be mono-, di- or trisubstituted by hydroxy, (C1-4)alkoxy, benzyloxy, halogen (F, Cl, Br, I), CF3, N3, (C1-4)alkyl, adamantyl, xe2x80x94SO2NH2, xe2x80x94NHCOCH3, xe2x80x94NHSO2CH3 or CH3SO2Oxe2x80x94 or by the bridge xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94); pyridyl or N-benzylpiperidyl;
or R3 and R4 together with the nitrogen atom to which they are bound represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, whilst the piperazinyl ring may optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di(C1-4)alkoxyphenyl, cyano-substituted phenyl, pyrimidinyl, phenyl(C1-4)alkyl, (C1-4)alkylphenyl or 
or the salts thereof with physiologically acceptable acids or complex-forming agents.
Compounds of formula I form tautomers of formula II 
The tautomers can be separated by known methods, e.g. by column chromatography or selective reduction (NaBH4 or catalytic reduction).
The compounds of formula II may occur in cis- and/or trans-form: 
If the structure of a compound is not expressly stated, the mention of formula I should be taken as including structure II as well.
In the definitions used in the text the radicals and groups may be identical or different, i.e. if one of the above-mentioned substituents occurs several times in a particular molecule, the meaning can be selected freely within the scope of the definitions provided.
The term alkyl means C1-6-alkyl and C1-4-alkyl radicals which may be substituted or, as alkyl radicals, are part of a functional group such as alkoxy or alkylthio. The alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl and tert.-butyl radicals as well as the various isomeric pentyl and hexyl radicals, such as e.g. isopentyl, neopentyl, n-pentyl and n-hexyl radicals.
The above definition thus also applies even when the alkyl radical itself is substituted and/or is itself part of an alkoxyalkyl-, alkoxycarbonyl-, alkoxy-, alkylthio-, alkylsulphonyl-, monoalkylamino-, alkylmethyl-, alkylthiomethyl- or dialkylamino- group or the alkyl radical, as a substituent, is bound to an aromatic heterocyclic or carbocyclic system.
The halogens are fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine and, to a lesser extent, iodine.
C3-6-cycloalkyl indicates cyclopropane, cyclobutane, cyclopentane and cyclohexane.
C5-6-cycloalkenes denote e.g. cyclopentene, cyclohexene and cyclohexadiene.
C3-6-alkynes are the isomeric hexenes, pentenes, butynes and propynes, preferably propargyl.
The C3-6-alkenes are the isomeric hexenes, pentenes, butenes and propenes, preferably allyl.
A preferred aspect of the invention consists of compounds of general formula I wherein
A denotes a benzo- or thieno group;
wherein, if A is benzo, m is 2, the R2s are in positions 6 and 7 and independently of one another represent hydroxy, (C1-4)alkoxy, benzyloxy, halogen (F, Cl, Br, I), (C1-4)alkyl, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R2 may together represent xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94; and if A is thieno, m is zero;
R1 denotes thienyl or the group 
xe2x80x83wherein
R7, R8 and R9 independently of one another may represent methyl, ethyl, propyl, phenyl or benzyl, whilst not more than 2 of the substituents can simultaneously represent phenyl or benzyl;
R3 and R4 independently of each other represent
(a) hydrogen,
(b) branched or unbranched C3-6-alkenyl,
(c) branched or unbranched C3-6-alkynyl, or
(d) branched or unbranched C1-12-alkyl, wherein the alkyl may be substituted by
hydroxy,
(C1-4)alkoxy,
di(C1-4)alkylamino,
furyl,
pyridyl,
pyrrolidinyl, N-methylpyrrolidinyl,
morpholino,
indolyl,
nitrilo,
thienyl,
adamantyl,
cyclohexyl,
phenoxy,
naphthyloxy or phenyl, whilst this phenyl or the phenyl contained in the phenoxy group may be mono-, di- or trisubstituted by hydroxy, (C1-4)alkoxy, benzyloxy, halogen (F, Cl, Br, I), CF3, N3, (C1-4)alkyl, adamantyl, xe2x80x94SO2NH2 or xe2x80x94NHCOCH3 or by the bridge xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94;
or R3 denotes hydrogen and R4 denotes cyclohexyl, phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl;
or R3 and R4 together with the nitrogen atom to which they are bound represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, whilst the piperazinyl ring may optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di(C1-4)alkoxyphenyl, pyrimidinyl, phenyl(C1-4)alkyl or 
Preferably, A represents the annelated ring systems 
wherein R2 is as hereinbefore defined.
Also preferred according to the invention are compounds I wherein A is indolo and the other substituents are as hereinbefore defined, preferably NR3R4 is either morpholinyl or in NR3R4 R3 is hydrogen and R4 is C1-4-alkyl, which may be substituted as hereinbefore defined.
Of the compounds I wherein A is benzo, the preferred compounds are those wherein m is 2 and the two R2s independently of each other represent methoxy, hydroxy, benzyloxy, methyl or chlorine or together represent xe2x80x94OCH2xe2x80x94, whilst the two R2s are in positions 6 and 7, particularly those compounds wherein R2 is methoxy, hydroxy, benzyloxy or methyl, and especially those wherein both R2s are the same and represent hydroxy or methoxy.
Of the compounds I, the preferred compounds are those wherein R1 is tert.butyl.
Other preferred compounds of formula I are those wherein NR3R4 has one of the following meanings:
a) in NR3R4, R3 is hydrogen and R4 is C1-6-alkyl;
b) in NR3R4, R3 is hydrogen and R4 is branched or unbranched alkynyl having 3 to 6 (preferably 3) carbon atoms
c) in NR3R4, R3 is hydrogen and R4 is branched or unbranched alkyl having 1 to 4 (preferably 1 to 3, especially 2) carbon atoms, the alkyl being substituted by
methoxy,
dimethylamino,
pyrrolidinyl, N-methypyrrolidinyl,
morpholino,
thienyl,
adamantyl,
pyridyl,
N-benzylpiperidyl,
cyclohexyl,
phenoxy,
naphthyloxy or 1 or 2 phenyl, whilst this phenyl (if only one phenyl group is present) or the phenyl contained in the phenoxy group may be mono-, di- or trisubstituted by methoxy, ethoxy, benzyloxy, halogen (particularly Cl, I), CF3, N3, methyl, tert.butyl, xe2x80x94SO2NH2, or by the bridge xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94;
or R3 denotes hydrogen and R4 denotes cyclohexyl, phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl;
d) in NR3R4, R3 and R4 independently of each other represent methyl, ethyl, (CH2)1-4-phenyl (wherein the phenyl group may be substituted like the phenyl group specified in (c)
xe2x80x83preferably 
e) R3 and R4 together with the nitrogen atom to which they are bound denote piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, whilst the piperazinyl ring may optionally be N-substituted by methyl or benzyl;
particularly those wherein NR3R4 has one of the following meanings:
a) in NR3R4, R3 is hydrogen and R4 is C2-6-alkyl;
b) in NR3R4, R3 is hydrogen and R4 is CH2CCH;
c) in NR3R4, R3 is hydrogen and R4 is branched or unbranched C1-4-alkyl, wherein the alkyl is substituted by
methoxy,
dimethylamino,
N-methypyrrolidinyl,
thienyl,
adamantyl,
phenoxy,
naphthyloxy or 1 or 2 phenyl, whilst this phenyl (if there is only one phenyl group present) or the phenyl contained in the phenoxy group may be mono-, di or trisubstituted by methoxy, ethoxy, N3, methyl, tert.butyl or xe2x80x94SO2NH2;
d) in NR3R4, R3 and R4 independently of each other represent methyl, ethyl, (CH2)1-4-phenyl
(wherein the phenyl group may be substituted by F) or particularly 
e) R3 and R4 together with the nitrogen atom to which they are bound are piperazinyl, N-substituted by methyl or benzyl.
Special mention should be made of compounds I wherein NR3R4 has one of the following meanings:
a) in NR3R4, R3 is hydrogen and R4 is ethyl, tert.butyl or (CH2)1 or 2xe2x80x94C(CH3)3;
b) NR3R4 is NHCH2CCH;
c) in NR3R4, R3 is hydrogen and R4 is ethyl, propyl or methylpropyl which is substituted by phenyl, which may be mono-, di- or trisubstituted by methyl or methoxy or monosubstituted by tert.butyl;
d) in NR3R4, R3 and R4 are identical, namely 
e) NR3R4 is 
particularly those wherein R3 is hydrogen or (C1-4)alkyl-phenyl and R4 is (C1-4)alkyl-phenyl, whilst in these groups C1-alkyl is preferably present and phenyl is mono-substituted by halogen (preferably Cl or F), CF3, methoxy or ethoxy, this substituent preferably being in the o-position.
The compounds of formula I may be prepared by methods known per se, preferably analogously to the method described in German Patent Application P 37 18 570.5, EP 358 957, EP 37 934, EP 251 794 and EP 288 048.
In the presence of a condensing agent, a malonic acid diamide of general formula IV 
wherein R1, R2, R3, R4 and m are as hereinbefore defined and Ar represents phenyl, indolyl or 2- or 3-thienyl, may be cyclised to obtain the corresponding compounds.
Suitable condensing agents for this process are strong Lewis acids such as phosphorusoxychloride, phosphoruspentachloride, phosphorustrichloride, phosphoruspentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride, as well as inorganic acids such as polyphosphoric acid, sulphuric acid, fluorosulphonic acid and hydrofluoric acid, or mixtures of condensing agents such as a mixture of phosphorusoxychloride and phosphoruspentachloride, or a mixture of phosphoruspentoxide and (C1-4)alkylsulphonic acid, e.g. with a P2O5xe2x80x94 content of about 10% by weight.
The cyclisation may be carried out in the presence or absence of a solvent. Any inert solvents are suitable provided that they have sufficient solubility for the reactants and a high enough boiling point, e.g. benzene, alkylbenzenes (e.g. toluene, xylene), chlorobenzenes, chloroform, acetonitrile and decaline. According to a preferred embodiment of the process the condensing agent used is phosphorusoxychloride in admixture with acetonitrile or a mixture of (C1-4)alkylsulphonic acid and phosphoruspentoxide, without the addition of solvents.
Preferably, the cyclisation is carried out with phosphorusoxychloride/acetonitrile or in difficult cases with a mixture of phosphoruspentoxide and C1-4-alkylsulphonic acid (preferably methanesulphonic acid). The reaction can be carried out in a wide temperature range, preferably with heating to 50xc2x0 C. up to the boiling point of the reaction mixture.
The necessary reaction period will be between 2 and 15 hours depending on the starting compound IV.
The 3-thiophenmalonic acid required for this preparation is commercially available. The 2-thiophenmalonic acid may be prepared by methods known per As (e.g. from 2-thiophenacetic acid using the carbonate method or from 2-thiophenbromide and diethylmalonate).
The compounds of formula I are bases and can be converted in the usual way with inorganic or organic acids and salts and complex-forming agents into any desired physiologically acceptable adducts (salts).
Acids suitable for salt formation include for example hydrochloric, hydrobromic, hydriodic, hydrofluoric, sulphuric, phosphoric, nitric, acetic, propionic, butyric, caproic, valeric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, p-hydroxybenzoic, phthalic, cinnamic, salicylic, ascorbic, methanesulphonic acid and the like.
The compounds may be administered by oral, parenteral or topical route. The desired therapeutic dose depends on the indication and formulation used and can be determined experimentally. Suitable forms include, for example, tablets, capsules, suppositories, solutions, syrups, emulsions, aerosols or dispersible powders. Tablets may be produced, for example, by mixing the active substance or substances with known excipients, e.g. inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for obtaining delayed release, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate. The tablets may also consist of several layers.
Coated tablets may be produced analogously by coating cores made in the same way as the tablets with substances conventionally used for tablet coatings, e.g. collidone or shellac) gum arabic, talc, titanium dioxide or sugar. In order to obtain delayed release or avoid incompatibilities the core may also consist of several layers. Similarly, the tablet coating may consist of several layers to achieve delayed release, whilst the excipients mentioned for the tablets may be used.
Syrups containing the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with ethylene oxide or preservatives such as p-hydroxybenzoates.
Injectable solutions are produced in the usual way, e.g. by adding preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylene diamine tetraacetic acid, and are then transferred into injection vials or ampoules.
Capsules containing one or more active substances or combinations of active substances may be prepared for example by mixing the active substances with inert carriers such as lactose or sorbitol and encapsulating them in gelatine capsules.
Suitable suppositories may be produced for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or derivatives thereof.
The compounds may be administered both enterally and parenterally. A proposed dose for oral use is 0.1 to 500 mg of active substance per dose and from 0.05 to 150 mg per dose for intravenous administration. The desired therapeutic dose depends on the indication and formulation used and can be determined experimentally.
The pharmaceutical compositions are suitable for oral or parenteral and possibly topical application. The chief formulations used are plain or coated tablets, ampoules and syrups. The single dose using these formulations is between 1.0 and 200 mg, preferably 20 to 50 mg per 75 kg of body weight. Generally, 1 to 3 single doses are required per day, depending on the gravity of the case.